THALASSEMIA MANAGEMENT Monitoring Deferasirox Therapy Ashutosh Lal, MD, UCSF Benioff Childrenʼs Hospital Oakland CHECKLISTS

SIDE EFFECT MONITORING FREQUENCY ACTION#

Reduced renal Serum creatinine 3-4 weeks • Lower dose by 25% if >33% increase over function baseline at 2 consecutive visits • Lower dose by 50% for 1 week if > upper limit of normal (ULN) • Increase gradually to previous dose if tolerated. • Interrupt therapy if creatinine >2x ULN

Renal tubular Serum potassium, 3-4 weeks • Lower dose by 25% if potassium, bicarbonate dysfunction phosphorus and or phosphorus are < lower limit of normal on bicarbonate 2 consecutive visits • Interrupt treatment for 1 week or more for severe deficits

Proteinuria Urine protein: 3 months • Confirm any urine dipstick 2+ or higher creatinine ratio with spot urine protein:creatinine or (or albumin: albumin:creatinine ratio creatinine) • If urine protein: creatinine ratio >0.5 g/g (or albumin:creatinine >300 mg/g) on 2 consecutive samples one month apart, lower dose by 50% and consider nephrology evaluation • Explore alternative causes for proteinuria

Elevated Alanine 3-4 weeks • Lower dose by 25% if ALT>3x ULN on 2 transaminases, aminotransferase consecutive visits but normal at (ALT) • Interrupt therapy if ALT>10x ULN or direct baseline bilirubin >2x ULN • Explore alternative causes for elevated ALT

Elevated Alanine 3-4 weeks • Lower dose by 50% in individuals with chronic transaminases aminotransferase viral hepatitis or marked liver iron burden if at baseline (ALT) further elevation in ALT (>2x from baseline value and >5x ULN) on 2 consecutive visits (see literature review) • If ALT does not improve after one month of holding DFX, the higher dose may be resumed

Retinopathy Retinal 12 months • Specialty evaluation to rule out alternative examination etiology if abnormal

Drug Concomitant 3-4 weeks • Evaluate potential interaction with initiation of interactions drugs any new drug (see literature review)

#Action: Consultation with a comprehensive thalassemia center is recommended if a toxicity is recurrent or causes interruption of treatment Deferasirox (DFX) is available in three formulations: defera- unknown as severe iron overload also causes hepatic in- sirox dispersible tablets (Exjade), deferasirox tablets (Jadenu flammation. Establishing baseline liver function is important tablets) and deferasirox granules (Jadenu Sprinkle). Guid- (particularly when liver iron concentration exceeds 15 mg/g ance for monitoring of deferasirox therapy is derived from dry weight) to avoid unnecessary reductions in dose. The clinical trials, case reports, and FDA-approved prescribing larger studies have reported persistent elevated alanine information. Monitoring the toxicity of chelation drugs is transaminase (ALT) in 1-6% of patients on DFX treatment. essential for patient safety and treatment efficacy in the long These elevations were usually mild, but 1-3% of patients term. Regular monitoring increases the likelihood that chela- experienced increase in serum ALT levels over ten times tion therapy will not require dose interruption. Some toxic- the upper limit.11 Cholestasis is reported in an occasional ities are independent of iron burden, while others may be patient,6 but is very rare. Deferasirox is contraindicated in more frequent with low iron burden. The risk of toxicity also patients with severe liver disease (Child-Pugh C), and should varies with age, diagnosis, intercurrent illness, and baseline be administered at a 50% reduced dose in those with mod- organ function. erate (Child-Pugh B) dysfunction.12 Individuals starting on deferasirox should be monitored In clinical practice, the most frequently encountered toxicity for skin rash and gastro-intestinal symptoms. Deferasirox of DFX is renal dysfunction. This can take various forms, in- should be stopped if skin rash develops, but can be rein- cluding elevated creatinine, proteinuria and proximal tubular troduced at a lower dose with oral steroids given for 2-3 dysfunction. The use of DFX is contraindicated in patients weeks. Severe skin reactions, such as Stevens-Johnson with creatinine clearance <40 ml/min.12 Increase in serum syndrome and erythema multiforme should result in per- creatinine is relatively frequent and may require reduction manent discontinuation of the drug. The GI adverse events in dose. The incidence of transient creatinine elevation is are less frequent with Jadenu tablet than with Exjade DT, 32-38% in clinical trials,13,14 with dose reduction in 13% of which have included pain, diarrhea and bloating. Uncom- subjects.14 Acute renal failure can develop if the dose is not mon, but serious side effects of DFX are serious GI bleed- modified, though its incidence is <1%.13 Proteinuria occurs ing (ulceration or perforation), hepatic toxicity (including in 6% cases but the need for dose reduction due to per- hepatic failure), renal toxicity (including acute renal failure), sistent high-level proteinuria is rare.10,15,16 Tubular dysfunction renal tubular acidosis (Fanconiʼs syndrome), and cytopenias or Fanconiʼs syndrome, manifesting as urinary electrolyte (particularly with preexisting bone marrow disorders). Elderly wasting and glycosuria, has been described in multiple case patients are more susceptible to serious adverse reactions. reports,17–23 with an incidence of 8% in one clinical trial,24 but It is recommended to hold deferasirox for a few days during rare in others.13 Tubular dysfunction is more common in pedi- any febrile or diarrheal illnesses. atric patients with relatively low body iron.12 The occurrence of febrile infection and dehydration, such as from diarrheal Summary of Literature Review: illness, can uncover or increase severity of acidosis that may require urgent attention. Low serum phosphorus and potas- Jadenu contains the same active ingredient as Exjade, and sium are commonly described in this setting.21,22 the two are similar except that Jadenu has 36% greater bio- availability and 30% higher peak serum concentrations.1 The Skin rash can occur at the beginning of treatment with DFX 14,25,26 dose of Jadenu is 70% of comparable Exjade dose, which is in 4-17% of patients, but is transient in most cases, an important consideration when patients switch between allowing continuation of therapy with or without a brief formulations. The bioavailabilty and peak and trough serum interruption. In post-marketing experience, Stevens-Johnson concentration of DFX are increased when it is taken with syndrome, toxic epidermal necrolysis, alopecia, anaphylactic 12 fat-containing meal,2 though this has not been observed to reactions, vasculitis and angioedema have been reported. change the frequency of side effects.3 Severe immune or cutaneous reactions preclude further therapy. Other rarely seen side effects are lenticular opac- A common side effect of Exjade is gastrointestinal discom- ities and, possibly, hearing loss6,27,28 Deferasirox is contra- fort in up to one-third of individuals manifesting as nausea, indicated during pregnancy and lactation. Deferasirox may 4–11 abdominal pain or diarrhea. These side effects appear interact with other drugs due to its effect on cytochrome to be less with Jadenu from experience and supported by P450 enzymes (such as induction of CYP3A4 and CYP2C8), 4 patient-reported outcomes in a study. A serious side effect and its metabolism by UDP-glucuronosyltransferase (UGT). of deferasirox is occurrence of GI hemorrhage. GI bleed- A complete list of these agents is available with deferasirox ing is believed to be more common in elderly patients with prescribing information and through programs to analyze thrombocytopenia secondary to malignancies, and its use in drug interactions. such cases is contra-indicated if platelet count is <50 x109/L. Cases of bleeding from gastric or duodenal ulcer in individ- uals with thalassemia lacking these risk factors are rare but References for this checklist can be found online at the serious.5–8 Cooley’s Anemia Foundation’s website: A minority of patients experience elevation in transaminases www.thalassemia.org/checklists-references. during DFX treatment,6,9–11 although the true incidence is The Cooley’s Anemia Foundation encourages doctors to utilize this information in treating thalassemia patients.

This project was supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant number U1AMC28550 (Thalassemia). This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government.